Project Summary Parkinson's disease (PD) is the second most common neurodegenerative disease of aging. Mutations in LRRK2 are associated with both inherited and sporadic forms of PD. LRRK2 is highly enriched in spiny projection neurons (SPN) in the dorsal striatum. However, the physiological role of LRRK2 in SPNs remains elusive. Our previous observations suggest a linkage between the pathogenic R1441C mutation and aberrant PKA signaling in SPNs. However, the analyses were limited by the inherent resolution provided by conventional biochemical approaches and microscopy. In this proposal, we seek to provide more precise information about the pathophysiological consequences of LRRK2 mutations in SPNs. In particular, it is our central hypothesis that LRRK2R1441C mutation leads to aberrant dopaminergic signaling in SPNs. The resultant striatal dysfunction, in turn, contributes to the symptomatology of PD. To pursue this, we will examine if LRRK2R1441C mutation alters dopamine signaling, corticostriatal transmission, corticostriatal plasticity, and excitability in SPNs through PKA signaling dysregulation. Moreover, assessment of striatal-dependent motor learning along with pharmacological manipulations will provide insight on the effects of LRRK2R1441C mutation in a whole-animal setting. In conjunction with standard cellular, molecular, and electrophysiological approaches, our investigations will capitalize on a combination of cutting-edge approaches that overcome obstacles that have impeded progress to date. These include, LRRK2 mutant mice, striatal pathway-specific (Cre and reporter) mice, viral gene delivery, and super-resolution imaging. The successful achievement of these aims will significantly advance our understanding of the mechanisms underlying PD, and in doing so, will promote the development of new therapies for PD patients in the future.